similarity searches of initial hits using databases of compounds
from your commercial suppliers (analoging by cataloging) or
large databases (such as the ZINC database:http://zinc.doc
king.org/search/structure).- Compounds should be screened for potential problems includ-
ing PAINS groups [16], mutagenic groups and groups with
known toxicity issues. - While maintaining broad chemical diversity, the library can be
screened through pkCSM and used to enrich particular ADMET
features favorable for the target protein/disease (e.g., BBB per-
meability for neuroactive compounds [12, 17–19]).
3.4 Modifications to
Improve ADMET
Properties
- pkCSM predictions can be used when composing screening
libraries, enriching them with compounds that suit the drug
target. For example, when screening for neuroactive com-
pounds, it would make sense to enrich your screening libraries
for compounds with high blood–brain barrier and central ner-
vous system permeability. - However, when a lead compound has been identified, there are
chemical modifications that can be performed which may
improve the pharmacokinetic and toxicity profile. Small struc-
tural modifications can significantly affect the pharmacokinetic
and toxicity properties of drug candidates. - Using the multiple molecule prediction mode of pkCSM, large
libraries of analogues can be screened to identify compounds
with promising ADMET profiles. A few common medicinal
chemistry strategies used to improve pharmacokinetic profiles
are described below. It is always worth bearing in mind how any
proposed alterations might affect how the compound binds to
the target of interest. While sometimes a successful strategy,
there are many times when new cores will need to be explored
in order to move away from these unfavorable properties.
(a) Improving oral bioavailability: Oral bioavailability is a func-
tion of the proportion of a drug absorbed through the
intestine, and the amount that is metabolized in the liver
before entering the systemic circulation. Passive intestinal
absorption correlates with size, with absorption decreasing
as molecules polar surface area increases beyond 60 A^2 ,
with negligible absorption observed beyond 140 A^2.
Charged and hydrophilic compounds absorb best when
their molecular weight is below 200 Da, and hydrophobic
compounds need to be at least partially water soluble.
(b) Improving metabolism profile: High levels of cytochrome
P450 metabolism will reduce oral bioavailability and
plasma half life [20]. This can be reduced through altering
the logP and PSA, and by blocking hydroxylation through
278 Douglas E. V. Pires et al.